Chemical Biology Discussion Group Year-End Symposium

FREE

for Members

Chemical Biology Discussion Group Year-End Symposium

Wednesday, June 5, 2013

The New York Academy of Sciences

Presented By

 

Chemical biology is a diverse and dynamic field involving chemical approaches to studying and manipulating biological systems. The goal of the Academy's Chemical Biology Discussion Group meetings is to enhance interactions among local-area laboratories working in chemical biology and to feature forefront research in chemical biology to the wider community. The meeting traditionally covers a range of current topics in chemical biology, including chemical probe development, organic synthesis, biosynthesis, protein engineering, nanotechnology, and drug discovery. The annual year-end meeting features distinguished keynote speaker Professor Alanna Schepartz of Yale University. This will be followed by shorter, cutting-edge talks by graduate students and postdoctoral fellows selected from participating tristate-area institutions, and a poster session.

*Reception to follow.

Registration Pricing

Member$0
Student/Postdoc Member$0
Nonmember$40
Nonmember (Student / Postdoc / Resident / Fellow)$20

 


The Chemical Biology Discussion Group is proudly supported by   American Chemical Society


Mission Partner support for the Frontiers of Science program provided by   Pfizer

Agenda

* Presentation times are subject to change.


Wednesday, June 5, 2013

11:30 AM

Registration and Poster Set-up

12:00 PM

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
Akira Kawamura, PhD, Hunter College, CUNY

12:10 PM

Bioorthogonal Labeling of Substrates of Type I Protein Arginine Methyltransferases (PRMTS) by Engineered Enzymes
Han Guo (Luo lab, Memorial Sloan-Kettering Cancer Center)

12:30 PM

The Design and Characterization of Helical Protein Fibers
Rudy Jacquet (Montclare lab, NYU-Poly)

12:50 PM

The Ultrafast Split Inteins and their Use in Modern Protein Semisynthesis
Neel Shah (Muir lab, Princeton University)

1:10 PM

Aldehyde Capture Ligation for Synthesis of Peptides and Proteins
Monika Raj, PhD (Arora lab, NYU)

1:30 PM

Coffee Break and Poster Session

2:30 PM

RNA Mimics of Red Fluorescent Protein
Wenjiao Song, PhD (Jaffrey lab, Weill Medical College, Cornell University)

2:50 PM

Structure of the Arginine Methyltransferase PRMT5-MEP50 Reveals a Mechanism for Substrate Specificity
Carola Wilczek, PhD (Shechter lab, Albert Einstein College of Medicine)

3:10 PM

Keynote Presentation: Visualizing Information Transfer through the Plasma Membrane
Alanna Schepartz, PhD, Yale University

4:10 PM

Networking Reception and Poster Session

5:00 PM

Close

Speakers

Organizers

Akira Kawamura, PhD

Hunter College, CUNY

Akira Kawamura received his B.Sc. and M.Sc. degrees in Organic Chemistry at the University of Tokyo. Attracted to the magnetic character of Professor Koji Nakanishi, Akira crossed the Pacific Ocean in 1994 to join the chemistry Ph.D. program at Columbia Univeristy. He received his Ph.D. under the direction of Koji Nakanishi and Nina Berova in 1999.

Before joining Hunter College, he spent his postdoctoral stint in the group of Peter G. Schultz at the Scripps Research Institute (1999-2002). Akira is currently an associate professor of chemistry at Hunter College, conducting research in bioorganic and natural products chemistry.

Jonathan Lai, PhD

Albert Einstein College of Medicine

Jon Lai is Associate Professor of Biochemistry at the Albert Einstein College of Medicine, Bronx, NY. His group's principal interests are in peptide and protein engineering strategies for biomedical applications. A major recent focus has been the development of antibody phage display technologies, and their application to a wide variety of targets such as viruses and oligosaccharides. Another area of interest is understanding viral glycoprotein function using a combination of structural and mutagenesis studies. Dr. Lai received his B. Sc. (Hons.) in Biochemistry from Queen's University in Kingston, Ontario, Canada in 1999, then his Ph. D. in Biophysics and Chemistry from the University of Wisconsin (Madison) in 2004 where he studied peptide structure and function. From 2004-2007 he performed post-doctoral studies at Harvard Medical School in enzymology and X-ray crystallography before beginning his independent position at Einstein.

Jennifer Henry, PhD

The New York Academy of Sciences

Keynote Speaker

Alanna Schepartz, PhD

Yale University

Alanna Schepartz, PhD, is the Milton Harris '29 PhD Professor of Chemistry and Professor of Molecular, Cellular, and Developmental Biology at Yale University.

Professor Schepartz was born on January 9, 1962 in New York City and was graduated from Forest Hills High School in 1978. After receiving a BS degree in Chemistry from the State University of New York–Albany in 1982, Alanna carried out graduate work at Columbia University under the supervision of Ronald Breslow. Following postdoctoral work with Peter Dervan at the California Institute of Technology, she joined the faculty at Yale University in July of 1988. She was promoted to Associate Professor in 1992, to Full Professor with tenure in 1995, and was named the Milton Harris, '29 PhD Professor of Chemistry in 2000. From 2002–2007, she held a Howard Hughes Medical Institute Professorship. In 2011, she was appointed as the Director of the Yale Chemical Biology Institute.

Alanna Schepartz is well known for the creative application of chemical synthesis and principles to understand and control biological recognition and function. Her research has contributed to and shaped thinking in multiple areas, including the molecular mechanisms of protein–DNA recognition and transcriptional activation; protein design and engineering and their application to synthetic biology; and the mechanisms by which chemical information is trafficked across biological compartments. She is also widely recognized for her design of the first and only example of protein-like architecture that lacks even a single α-amino acid.

Alanna Schepartz has received a number of awards for her work, including a David and Lucile Packard Foundation Fellowship (1990), a N.S.F. Presidential Young Investigator Award (1991), a Camille and Henry Dreyfus Teacher–Scholar Award (1993), an Alfred P. Sloan Research Fellowship (1994), an A.C.S. Arthur C. Cope Scholar Award (1995), the A.C.S. Eli Lilly Award in Biological Chemistry (1997), the Dylan Hixon '88 Award for Teaching Excellence in the Natural Sciences (1999), the Agnes Fay Morgan Research Award (2002), the Frank H. Westheimer Prize Medal (2008), the ACS Chemical Biology Prize & Prize Lecture (2010), for which she was the inaugural recipient, the Alexander M. Cruickshank Prize (2010) and the Ronald Breslow Award for Achievement in Biomimetic Chemistry (2012). In 2010, Schepartz was elected as a Fellow of both the American Academy of Arts & Sciences and the American Chemical Society. Since 2005, she has served the chemical biology community as an Associate Editor of the Journal of the American Chemical Society.

Speakers

Han Guo

Luo lab, Memorial Sloan–Kettering Cancer Center

Han Guo is a fourth year graduate student from the Tri-Institutional Training Program in Chemical Biology (TPCB). Born in China, he came to the U.S. in 2005 to attend Bowdoin College. During his undergraduate study, Mr. Guo worked in Dr. Danielle Dube’s lab and developed a strong interest in Chemical Biology from his project of developing chemical tools to target Helicobacter pylori glycosylation through the synthesis of azide-containing glycans, which was supported by the HHMI summer fellowship. In 2009, he received his B.A. in Biochemistry and German, and became a member of the Phi Beta Kappa Society. Mr. Guo joined Dr. Minkui Luo’s lab at Memorial Sloan Kettering Cancer Institute in 2010 and is currently working on the development of Bioorthogonal Profiling of Protein Methylation (BPPM) to understand the biological functions of type I Protein Arginine N-methyltransferases (PRMTs) by identifying their cellular substrates.

Rudy Jacquet

Montclare lab, NYU–Poly

Rudy Jacquet is a Master’s student in biotechnology at NYU-POLY. My goal is to one day contribute to the pharmaceutical and biotech industry. Having obtained my bachelor’s degree in biology at Lehman College and the opportunity right after to conduct research at University of Michigan, my desire for scientific research goes as back as I can remember. Now, moving forward, this desire has led me to the exploration of new research area such as protein engineering. Whereas before I was exposed to biomedical research, currently I am learning the great potential that research in the material sciences hold for the advancement of our society. Thus, as the son of Haitian immigrants and the first of my family to graduate college, I have cherished the opportunities granted so far to me. With each new stride and exploration I have made, beginning with my fascination of the sciences from my classes to working at the bench, my motivation toward scientific research grew. I am thankful for having the opportunity to contribute to scientific research. A field that is highly interesting, valuable and grand.

Neel Shah

Muir lab, Princeton University

Neel Shah received his B.S. in Chemistry in 2008 from New York University. At NYU, he worked in Professor Kent Kirshenbaum’s lab and developed a novel method for constraining the backbone conformations of a class of peptidomimetic oligomers. After obtaining his undergraduate degree, he began his graduate studies at The Rockefeller University under the advisement of Professor Tom Muir. Neel moved with the Muir lab to Princeton University in 2011 and is currently carrying out his doctoral research on the biochemical and biophysical characterization of naturally split inteins.

Monika Raj, PhD

Arora lab, NYU

Monika Raj is a postdoc at New York University in the Arora Lab. Born in India; she completed her Phd in field of Organocatalysts from Indian Institute of Technology, one of the premier institutes in India. Monika spent a brief amount of time as a postdoc at the University of Pennsylvania with Prof. Barry Cooperman. At UPenn, her work was focused on developing the protein sequence monitoring technology. Through this effort, she completed determining the mechanism and distribution of fluorescent labeling of tRNA. Currently, in the Arora lab at NYU, Monika is working towards the development of new methodologies and auxiliaries to carry out ligation of peptides, proteins and peptidiomimetics.

Wenjiao Song, PhD

Jaffrey lab, Weill Medical College, Cornell University

Wenjiao Song joined Dr Jaffrey’s lab at Weill Cornell Medical College as a postdoctoral associate in July, 2010. Since coming to Dr Jaffrey’s lab, she has developed a strategy to make RNAs that recognize specific proteins and undergo conformational changes that result in the RNAs becoming fluorescent. This work is currently under review at Nature Methods. She currently is developing a new class of RNA molecules which bind to and activate the fluorescence of fluorophores that resembled those that naturally occur in red fluorescent proteins found in coral. Before joining Dr Jaffrey’s laboratory she has an extremely successful graduate experience in the laboratory of Qing Lin at SUNY Buffalo, where she focused on new methods for protein modification and conjugating proteins with fluorescent dyes in living cells. Wenjiao’s work led to numerous peer-reviewed papers, including four first-author papers in journals such as the Journal of the American Chemical Society, Angew. Chemie, and ACS Chemical Biology.

Carola Wilczek, PhD

Shechter lab, Albert Einstein College of Medicine

Carola Wilczek received her diploma (master) in chemistry from the Westfaelische Wilhelms-University (WWU) in Muenster, Germany in 2005. She did her PhD at the WWU in the laboratory of Karl-Heinz Klempnauer studying changes in chromatin structure caused by the transcription factor and oncogene c-Myb. Carola’s postdoctoral work at Albert Einstein College of Medicine in David Shechter’s laboratory focuses on understanding the mechanism of the essential histone arginine methyltransferase complex PRMT5-MEP50.

Sponsors

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The Chemical Biology Discussion Group is proudly supported by   American Chemical Society


Mission Partner support for the Frontiers of Science program provided by   Pfizer

Abstracts

Bioorthogonal Labeling of Substrates of Type I Protein Arginine methyltransferases (PRMTs) by engineered enzymes
Han Guo, Molecular Pharmacology and Chemistry Program & Tri-Institutional Training Program in Chemical Biology, Memorial Sloan Kettering Cancer Institute

Protein arginine methyltransferases (PRMTs) transfer the methyl group from S-adenosyl-L-methionine (SAM) to the guanidino nitrogens of specific arginine side chains. Type I PRMTs such as human PRMT1, 2, 3, 4, 6 and 8 catalyze the formation of ω -NG-monomethylarginine (MMA) and asymmetric ω -NG, ω -NG-dimethylarginine (ADMA), and share a conserved SAM-binding pocket. These PRMTs can have distinctive subcellular localizations and substrate specificities. Dysregulation of these processes has been linked to human diseases including cancers. However, elucidating the pathogenic roles of the dysregulated PRMTs is largely hindered by ambiguous substrate profiles of these PRMTs. Inspired by the emerging Bioorthogonal Profiling of Protein Methylation (BPPM) using engineered methyltransferases and SAM analogues for target identification, we systematically explored the SAM-binding pocket of type I PRMTs and identified a common Met-to-Gly mutant suitable for BPPM. This mutant transforms the type I PRMTs into promiscuous alkyl-transferases with sp2-β-sulfonium-containing SAM analogues as alternative cofactors. With the promiscuous Met-to-Gly variants and the matched 4-propargyloxy-but-2-enyl (Pob)-SAM or (E)-hex-2-en-5-ynyl (Hey)-SAM analogues as the BPPM reagents, we were able to identify hundreds of novel protein targets in HEK293T cells for the 5 type I PRMTs. The revealed targets of PRMTs and the transformative character of BPPM present unprecedented opportunities toward elucidating physiological and pathological functions of PRMTs.
 

Co-Author: Minkui Luo, PhD, Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Institute, and Tri-Institutional Training Program in Chemical Biology, Memorial Sloan Kettering Cancer Institute

The Design and Characterization of Helical Protein Fibers
Rudy Jacquet, Department of Chemical and Biological Engineering, Polytechnic Institute of New York University

The design of protein fibers that are able to self-assemble is important in the field of biomaterial science. From generating biomaterials with better applicability (as in electronics or optics) to furthering our understanding of protein folding and assembly, the design of self-assembled proteins is crucial in these fields. We have designed and generated protein fibers composed from two complementary alpha helical proteins referred to as CC and Q54. These two protein monomers self-assemble longitudinally via interactions between sticky ends. Our results show that the fibers generated are alpha helical and are formed through assembly of a pentameric coiled coil structure. These fibers are able to bind the small molecule curcumin within the hydrophobic pore of the pentamer. In addition to secondary structure of the proteins the melting temperature of CC and Q54 fibers are determined. These protein fibers show great potential to be used for application in biosensors or as biomaterial scaffolds for the templation of inorganic metals.
 

Co-Authors: Jasmin Hume, Jennifer Sun, Jin Kim Montclare, Department of Chemical and Biological Engineering, Polytechnic Institute of New York University

Ultrafast Split Inteins and their use in Modern Protein Semisynthesis
Neel H. Shah, Princeton University

Inteins are invaluable tools for chemical biology. These protein domains, which facilitate the cleavage and formation of peptide bonds through (thio)ester intermediates, provide reactive handles for the chemical manipulation of virtually any protein of interest. Indeed, a number of wide-spread intein-based protein engineering tools have been developed over the past two decades. These include protein semisythesis techniques that can be applied in vitro and in vivo, methods to head-to-tail cyclize genetically encoded peptides and proteins, strategies for segmental isotopic labeling of proteins for NMR analysis, and tools to control protein function inside living cells and organisms. Despite these advances, traditional intein-based technologies are plagued by the slow reactivity and side reactions of commonly used inteins. Here, we describe the characterization of an entire family of naturally split inteins found in cyanobacteria. We demonstrate that many members of this family can carry out the multi-step protein splicing reaction in a few minutes rather than hours. Furthermore, we find that these inteins are abnormally efficient in their capacity to form reactive thioester intermediates. Taking advantage of these biochemical properties and the strong affinity between split intein fragments, we devised a streamlined procedure for the generation and purification of protein α-thioesters from cell lysates, rapidly with minimal side products. The products of this technology can be directly used as substrates for Expressed Protein Ligation to generate semisynthetic proteins. We show that this approach is amenable to the synthesis of a variety of proteins, including post-translationally modified histones and site-specifically modified monoclonal antibodies.
 

Co-Authors: Miquel Vila-Perelló, Zhihua Liu, Tom W. Muir, Princeton University

Aldehyde Capture Ligation for Synthesis of Peptides and Proteins
Monika Raj, Department of Chemistry, New York University

We have developed a readily accessible aldehyde capture ligation (ACL) for synthesis of polypeptides and proteins. By using this ACL approach, ligation can be carried out with any type of amino acids at N-terminal peptide, which is in contrast to traditional methods requiring cysteine residue1 or thiol containing amino acid derivatives2 at N-terminal peptide. By using ACL we can directly obtain the native amide bond at ligation site. Once the ligation is complete, auxiliary can be reused again for another set of ligations. This methodology circumvents the limitations associated with conventional methods.1,2 By ACL we can incorporate fluorescent probes, stable isotopes in the proteins and can study the behaviour of such artificial proteins inside the cell. By using this auxiliary we can also study various posttranslational modifications by ubiquitylation of proteins, important for intracellular processes such as kinase activation and endocytosis, with native isopeptide linkage.
 

Co-Authors: Huabin Wu, Paramjit S. Arora, Department of Chemistry, New York University
 
References:
1Dawson, P. E.; Muir, T. W.; Clark-Lewis, I.; Kent, S. B. Science 1994, 266, 776-779.
2 (a) Shang, S.; Tan, Z.; Dong, S.; Danishefsky, S. J. J. Am. Chem. Soc., 2011, 133, 10784–10786. (b) Yang, R. L.; Pasunooti, K. K.; Li, F. P.; Liu, X. W.; Liu, C. F. J. Am. Chem. Soc. 2009, 131, 13592-13597. (c) Harpaz, Z.; Siman, P.; Kumar, K. S. A.; Brik, A. Chem. Bio. Chem. 2010, 11,1232–1235. (d) Chen, J.; Wang, P.; Zhu, J. L.; Wan, Q.; Danishefsky, S. J. Tetrahedron 2010, 66, 2277-2280.
 

RNA Mimics of Red Fluorescent Protein
Wenjiao Song, PhD, Weill Medical College, Cornell University

Green fluorescent protein (GFP) and its derivatives have transformed the use and analysis of proteins for diverse applications. Recently, a new class of genetically encodable RNA mimics of GFP have been described which comprise short RNA aptamers that bind and switch on the fluorescence of otherwise nonfluorescent small molecule dyes. These include Spinach, a green fluorescent RNA-fluorophore complex that can be used for tagging and imaging RNA trafficking in living cells. However, for many imaging applications, it is valuable to have red, orange, or red fluorescence, due to the lower cellular autofluorescence background. To address this problem, we synthesized a series of fluorophores that resemble those found in red fluorescent protein (RFP) and its family members. These fluorophores extend the p-orbital conjugation of the original fluorophore used in Spinach. Using the SELEX (Systematic Evolution of Ligands by Exponential Enrichment) procedure, we have identified novel RNA sequences that bind and activate their fluorescence. Using this approach, we have obtained RNA-fluorophore complexes which exhibit fluorescence emission ranging from yellow to the near-infra red. In the case of our Corn, Carrot, and Radish tags, we obtain quantum yields comparable to fluorescent proteins. Furthermore, these RNA aptamer tags allow imaging of RNA in living cells. Together these data provide the first aptamer tags for labeling RNA in the red spectral range, and provide the opportunity for multiplexed RNA imaging in cells.
 

Co-Author: Samie R. Jaffrey, MD, PhD, Weill Medical College, Cornell University

Structure of the Arginine Methyltransferase PRMT5-MEP50 Reveals a Mechanism for Substrate Specificity
Carola Wilczek, Department of Biochemistry, Albert Einstein College of Medicine, Yeshiva University*

The arginine methyltransferase PRMT5-MEP50 is necessary for embryogenesis and is misregulated in a variety of cancers. We determined the crystal structure of full-length Xenopus laevis PRMT5-MEP50 complex in the presence of S-adenosylhomocysteine (SAH). PRMT5-MEP50 forms an unusual tetramer of heterodimers with substantial surface negative charge. Analytical ultracentrifugation, multi-angle light scattering, and small-angle X-ray studies are consistent with this assembly in solution. Each PRMT5-dimer pair is arranged in a head-to-tail fashion. The PRMT5 catalytic site is oriented towards the cross-dimer paired MEP50. MEP50 is required for PRMT5-catalyzed histone H2A and H4 methyltransferase activity and binds substrates independently, consistent with a role for MEP50 as a substrate presenter.
 
Histone peptide arrays and solution assays demonstrate that PRMT5-MEP50 activity is inhibited by substrate phosphorylation and enhanced by substrate acetylation. PRMT5-MEP50 methylates H2A/H2B dimers, H3/H4 tetramers, and octamers, but cannot methylate nucleosomes. Electron microscopy showed substrate density centered on MEP50. These data suggest a mechanism in which MEP50 binds substrate and presents it to the cross-dimer PRMT5 to align the substrate arginine in the active site, modulated by substrate post-translational modifications.
 

Co-Authors: Meng-Chiao Ho2*, Jeffrey B. Bonnano1, Li Xing3, Janina Seznec4, Tsutomu Matsui5, Lester G. Carter5, Takashi Onikubo1, P. Rajesh Kumar1, Man K. Chan1, Michael Brenowitz2, R. Holland Cheng3, Ulf Reimer4, Steven C. Almo1, and David Shechter1
 
1Department of Biochemistry, Albert Einstein College of Medicine, Yeshiva University
2Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
3Department of Molecular and Cellular Biology, University of California, Davis
4JPT Peptide Technologies, Berlin, Germany
5Stanford Synchroton Radiation Lightsource, SLAC National Accelerator Laboratory, California
*contributed equally

Visualizing Information Transfer Through the Plasma Membrane
Alanna Schepartz, PhD, Department of Chemistry, Yale University

Aberrant activation of the epidermal growth factor receptor (EGFR) is critical to the biology of many cancers. The molecular events that define how EGFR transmits and decodes extracellular ligand-binding events through the membrane are not fully understood. This lecture will describe the application of a chemical tool, bipartite tetracysteine display, to study ligand-dependent EGFR activation in mammalian cells. Our findings provide new insight into how multi-domain membrane proteins decode and transmit distinct extracellular signals to the cell interior.
 

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